Abstract
Elevated branched-chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA per se or hepatic mammalian target of rapamycin activation, but instead are due to a shift in the relative quantity of dietary BCAAs and other amino acids, notably tryptophan and threonine. Increasing the ratio of BCAAs to these amino acids results in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high-BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but instead are a consequence of hyperphagia driven by amino acid imbalance.
The role of macronutrients (proteins, fats and carbohydrates) in linking diets to health has been the focus of much research. Recent work has underscored the necessity of examining these links within a mixture framework, which is sensitive not only to the individual effects of macronutrients, but also to their interactive effects1. Protein, in particular, has been shown to interact powerfully with dietary fats and carbohydrates to influence health via effects on appetite and post-ingestive physiology. One such interaction, observed in many animals including humans, is ‘protein leverage’, where the strong appetite for protein causes the overconsumption of fats and carbohydrates when feeding on protein-dilute diets2,3. Another is the demonstration that the dietary ratio of protein to carbohydrate impacts reproduction, ageing, immune function, microbiome, late-life cardiometabolic health, brain health and lifespan4–7.
Proteins, however, are themselves complex mixtures of aminoacids that when modified can have profound effects on growth, early life health and longevity8–10. Restriction of specific aminoacids, such as methionine, mimic the health and lifespan effects of chronic dietary restriction, despite an increase in energy intake11. Indeed, most amino acids have important functions in metabolic health outside their role in protein synthesis. The branched-chain amino acids (BCAAs) Ile, leucine (Leu) and valine (Val) have assumed particular prominence, both because of their role in influencing insulin, insulin-like growth factor 1 (IGF1) and mammalian target of rapamycin (mTOR)—key pathways linking nutrition with health and ageing12—and also because their circulating levels are
positively associated with obesity, insulin resistance and metabolic dysfunction in rodents5,13–16 and with obesity, insulin resistance and type 2 diabetes in humans17–20. We previously reported that mice fed a high-protein, low-carbohydrate diet throughout life were hypophagic, metabolically impaired in late-life, had elevated circulating BCAAs, increased hepatic mTOR activation and reduced median lifespans compared to mice fed a low-protein, high-carbohydrate
diet5. These results suggest that health and ageing in mice can be altered by titrating the balance of macronutrients to influence circulating BCAA and mTOR activation. In this study, we sought to determine whether and how dietary BCAA manipulation influences healthspan and lifespan in mice.
We demonstrate that the metabolic and lifespan costs of high BCAA:non-BCAA intakes, when paired with a high-carbohydrate, low-fat nutritional background, are not associated with increased hepatic mTOR activation; rather, they can be explained by their branched interactions with other key metabolically essential amino acids leading to extreme hyperphagia. Rebalancing the amino acid profile in the diet with the addition of tryptophan (Trp) or threonine (Thr) suppressed food intake, whereas preventing hyperphagia in BCAA-supplemented diets through either 20% calorie restriction or pair-feeding reversed metabolic dysfunction and lifespan costs. These findings illustrate the complex nutritional interactions thatinfluence appetite signalling, metabolic health and lifespan in mice.
